Note: Descriptions are shown in the official language in which they were submitted.
~6 ~
PRIOR ART
There is disclosed in the prior art certain thiazol-
eneaze~idinones 1 of the formula:
R
.,. ~ .
/5 ..
R2 ~ ~H ,¦
0
C02R
" 2
wherein R stands for benzyl or phenoXymethyl, R stands for
hydrogen and Rl is a cleavable radical. The compounds since
.~ they are obtained from natural penlcillin G or V can thus only
` : yield corresponding cephems in any synthetic routes. These
; compounds thus provide a llmlted utility ln the synthesls of
t~ 10 cephalosporins and peniçillins.
.`~" . THE INYENTION
.~ .
`~ In accordance wlth the prese~nt invention there is
:ii `
provided a novel process for preparing thiazolenea~et~d1nones 1
~: : of the general ~ormula:
R :
` }
0
~ wh~r~1n~
?~i R st~nds for phenoxyl~weral~kyl, phenylthiolower-
alkyl, benzy:l~, lower alkyl, phenyl, heteroaryl, :
heteroarylmethyl, ~-amlnobenz~yl and protected
:derivatives~th~ereof, 4-am~no-4~carboxy-l-butyl
and protected derivdtives:thereQf, R30-, R3S-,: :
and~R3R4N~
~ 1
~ . ,
. .
~ia~
where
R3 is lower alkyl, phenyl, heteroaryl, or aryl-
loweralkyl.
; R4 is hydrogen or radical R3,
R is hydrogen or methoxy;
R1 is hydrogen, lower alkyl, loweralkoxymethyl,
aryloxymethyl, 2,2,2-trichloroethyl, benzyl, p-
; nitrobenzyl, benzhydryl, phenacyl, or trimethyl-
silyl.
Formula 1 is representative o~ the two isomers
depicted by la and lb.
R2~ ~ R2~
- ~ COOR1 1b ~I COOR
. The novel process oi the present inventlon ¢omprises
~ extruding sul~ur ~rom dithiazeneaæetidinones 2 o~ the ~ormula:
`.
.,~, : /r S~
R2 ~ 2
COOR
.
whero1n R, R1 and R2 are as dc~lned previously.
... ,~i ~ ~.
~ - 2 ~ :~
.~ .
A.
` ' ` . . ': : ' . '' : . " ' . . . ' . '. : ' :. ' '' ' " ' : " .'` . . .' ` ' ' . ' :' ''.' .' ''. ' " ''~ '' .` : ' `
~ 361~
The extrusion of sulfur from the dithiazeneazetidi-
nones 2 may be carried out in a number of ways. In accordance
with tbe present invention it is understood that the expression
"extrusion of sulfur" comprises any procedure which will
el~ectively remove one sulfur atom ~rom a dithiazeneazetidinone
2. Such proceduresinclude photolysis or heating or the use of
"sul~ur abstraction compounds" such as trivalent phosphorus
compounds or the use of compounds such as pyridinium dichloro-
methylphosphonate, Lewis acids, aqueous strong acids, iodine
and sulfenyl iodides. For example sulfur can be extruded by
photolysis or heating alone in a suitable solvent for a period
o~ time which depends on the compound 2 used. The solvent may
be an organic inert solvent such as dioxane. The abstraction
o~ sul~ur may also be carried out in the presence of water or
a catalyst such as pyridinium dichloromethylphosphonate or a
sullur abstra¢tion compound such as triphenyl phosphine,
: ",
trimethyl phosphite or tris(dimethylamine)phosphite. Also
extrusion of sul~ur ~rom the dithiazeneazetidinones 2 to the
desired thiazoleneazetidinones can be carried out by treatment
with iodine, sulfenyl iodides suoh as benzothiazole-2-sul~enyl
iodi~de or with metal salts (Lewis aoids) such as for example
antimony pentachloride or tin chloride 7 in an inert solvent
suoh as ~or example toluene, methylene chloride or dioxane;
and~aqueous strong acids such as for example methane sulfonic
acid.
Th~ choiG~ o~ ~he sul~ur eXtru~ion proaess will
depend on the value~o~ the suh~tituant ~. For example~when ~
st~nd~ ~or phenoxy (0O-) or~phenoxymethyl (0OCH2) the pr~ered
;~ reagent ior the conversion o-~ 2 to la is iodine or sul~enyl
iodides such as benzothiazole-2-sul~enyl iodide, ~ollowed by
; treatment with sodium thlosul~ate. ~ -
'
; - 3 -
~0~3~
The starting dithiazeneazetidinones 2 are convenient-
ly obtained from penicillin sulfoxide thioamides 3 of the
general formula:
2
Il R H
RCNH ~ ~
~ N ~ \ 3
; H COOR
The thiazoleneazetidinones 1, are particularly
useful intermediates in the preparation of cephalosporins and
penicillins. For example, the thiazoleneazetidinones 1 react
.. ,
with sulfenyl chlorides to form unsym-azetidinone disulfides,
3 (W.G.E. Underwood, Glaxo Labs Ltd., Ger. Offen. 2,303,889,
26 Jan. 1973), which upon reaction with iodine will form the
3-iodocephams 4, as disclosed in copending Canadian appl. Ser. ~ ;
No. 229,909, filed June 23, 1975 which upon dehydroiodination `
will provide the corresponding 3-cephems, 5. Also, the
thiazolineazetidinones 1, react with iodine or better sulfenyl
iodides in presence of moisture, to form the 3-iodocephams, 4 ~-~
which are readily dehydroiodinated to the 3-cephems, 5 (see
Flowsheet 1 below).
.,1 ' '.; ' . .
, ,
~ ! , , .:
~'`' ' ' :,,,, '
"`,(~ ,~,'. "'.. "
. " . .
:~'``~1 ', ', ' ~ ,'
~,5 - 4 ~ ;~
. , ... -~
63~
FLOWSHEET 1
RCNH~
COOR '
3 2 a COOR '
; ~ /
~:~ R ~/
. I
R~ CON~--
COOR '
.
3 or 2
R SH- I 2-N20R2 H
RcoNH ~ S
~3
.:j COOR '
Pyridine
/
~. ~ :
RCO~
COO~
, :
.:~
~; .
..~
~. -- 5 --
.,
~ .
~3 ~ ~
Also within the scope of the present invention are
those compounds where R stands for R30-, R3S-, and R3R4N-
wherein R3 and R4 are as previously defined. The advantage of
the new compounds where R stands for R30-, R3S-, and R3R4N-
over the known compounds where R stands for benzyl (0CH2-) or
phenoxymethyl (00CH2-) is that they are better suited to
certain chemical reactions usually employed in the chemical
modification of these compounds. Thus brominations employing
N-bromosuccinimide would be expected to give a cleaner product
with those compounds derived from 1 (R = R30-, R3S-, and
R3R4N- with R3 being phenyl and heteroaryl) while with
-~ compounds 1 (R = 0CH2, and 00CH2) bromination of the methylene
: .
! group would be an added complication.
The starting penicillin sulfoxide thioamides 3 are `
themselves obtained in a number of ways. The penicillin
sulfoxide thioamides 3 where R stands for R30-, R3S-, and
R3R4N-, and R2 stands for H may be conveniently obtained by
thioacylation of 6-aminopenicillanic acid sulfoxide with a
thioacylating agent corresponding to the following formulae:
RCSCl, RCSYR3, CS2/R3X, R3N=C=S, CSC12/R3R4NH, wherein R3 and
i ~ R~ are as previously defined, Y is sulfur or oxygen and X is
halogen. The thioacylation reaction is carried out in the
man`ner known in the art. This procedure is illustrated in
Flowsheet 2. It is also possible to obtain the penicillin
.. -
~ sulfoxide thioamides 3 wherein R stands for R30-, R3S- or
.~! R3R4N- by treating a 6-isothiocyanate of penicillanic acid
sulfoxide with an alcohol of the formula R30H, a thiol of the
formula R3SH, or a secondary amine of the formula R3R4NH.
~` :
. :, . . .
:1 ,
. .
i . .
' - 6 -
, . :. .
`` "` .' '' :.',
'
: ' . . ' . ~ ', ' ' . ., ` ' ' ' .
' ` ' ' .
636~
FLOWSHEET 2
R2 H
H2N~j S~CH1
C~N ~ H 3
`COOR
r l l
,. RCCl or RCYR3 I RN:C_S or R3R4NH/csrl2
Base/CS2/R X/R'~Y .-
Routa 1 Route 2
.~ ~ Route 3
q R ~ N H ¦ R 3 R 4 N C N H
`I:OOR `COO R
3 3 -:
~j \ / :~ .
5 R 2 H
R3SCNHT~--\<CH3
N ~ C H 3
. ~; : . :
i ~, :
.`'~ :
i3~
Alternatively, the penicillin sulfoxide thioamides
3, may be derived from Penicillin G, N or V sulfoxides in
which case R is benzyl when starting from penicillin G, R is
phenoxymethyl when starting from Penicillin V and R is 4-
amino-4-carboxy-1-butyl when starting from Penicillin N, in
which case it is preFerred to protect the amino group ~y
acylation and the carboxy group by esterification. The
preparation of the penicillin sulfoxide thioamides 3 may be
schematically illustrated by reference to Flowsheet 3.
., : .
'.
, .
~ -.
i .. ~
`, ''.'
,.
.`,`~ .,':
. . .
.. , - 8 - .
, ` '
.
3~
FLOWSHEET 3
O R 2 H
RC-NH~ \~<cH3
N C H 3
COORl
.. .
': PC~ ~;
`:' \ / "
"
"` Cl R2 ,~
',: I ' ' S
RC_N ~-- ~XCH 3
o~N C H 3
t~o R
l .
H 2 S
,;j
o : :
`' : S R 2 H ~
RCNH~H3
C O O R
. i
',:
`"3
` ~ ` ~ . :
. ,.j
~ . ` 9:~ ~ .
~ : .
i . ~ -
. . . .
,,
i~63~
More particularly, Penicillin G sul~oxide, Penicillin
N sulfoxide or Penicillin V sulfoxide 7 is chlorinated with a
suitable agent such as phosphorus pentachloride in the presence
o~ a base such as dimethylaniline or pyridine. 0ther procedures
~or the preparation of haloimines, 8, may also be used. The
chloroimine compound 8 is then readily trans-formed to its corre-
,, sponding thioamide 3 by reaction with hydrogen sulfide in the
, presence o-~ an acid catalyst such as hydrogen chlori,de or
; suliuric acid or the like.
~' It should be appreciated that the thiazoleneazetidi-
-- nones 1 of the present invention are useful intermediates for
the preparation o~ cephalosporins. For example, on treatment ,
,` ~With sulfenyl iodldes they provide 3-lodocephams whlch can be
~3~ converted to the cephem compounds, such as 7-ADCA (7-amino-
desacetoxycephalosporinic acid) by methods known to the art.
EXAMPLES
.. . .
: The present invention will be more readlly understood
by re~erring to the following Examples which are given only to
, .
illustrate the invention rather than limit its scope,
' EXAMPLE l
METHYL 6-PHENOXYTHIOACETAMIDOPENICILLANATE SULF02IDE
(R = 00CH2-, Rl = CH3)
Phosphorus pentachloride'(26.4 g., 0.126 molesj was
added in one lot to a stirred, cold (-70) solutio~ o-~ methyl ~ ,
penicillin V sul~oxide (45.0 g., 0.1185 mole) and dimethyl-
aniline (~36.3 g., 0.3 moles) in methylene ¢hloride~(600 ml).
and the mlxtur~ stirrod ~or ~'hrs. at -50 or lower. ~2S
jJ, ~
~-` is then bubbled lnto the reaction mixture at -70~ a~d a~ter
approximately ~ hr. the mlxture becomes a clear yellow ~rom
a olear dark brown colour. ~The H2S~is oontinued ~or 1 hr. at
~ 50 and the mixture warmed to 0 by applying an ice bath.
.: ``i: :
. . 1
.i , ' '
. . .
~ 3~
The H2S addition is continued at 0C. for 1 1/2 hrs, after
which the reaction mixture is poured into ice water (750 ml)
and the resulting mixture stirred with aqueous sodium bi-
carbonate (90 9. in 200 ml). The layers were separated and
the organic layer extracted sequentially with water (300 ml),
aqueous HCl (3 molar, 2 x 300 ml) and salt water (300 ml).
The organic layer was dried (MgS04), filtered and the filtrate
concentrated to a yellow powder, 44.5 g., which was estimated
; to contain about 60% of methyl 6-phenoxythioacetamido-
penicillanate sulfoxide from its nmr spectrum.
The crude thioamide was purified by column chroma-
tography over silica gel (Grace Davidson SMR7-1498 grade
951-MS, 450 9.) using chloroform as eluent and collecting
:` :
about 50 ml fractions. The process was monitored by tlc of
the fractions. Fractions 11 to 145 contained the thioamide
``` and were combined and concentrated to give 26.6 9. of the
`-, thioamide which was washed with methanol to give 22.8 9. of pure thioamide. An analytical sample was obtained by re-
crystallization from methanol as white crystals, m.p. 144-
20~ 145.
.. - . .
Analysis: Calcd. C 51.51, H 5.05, N 7.07, S 16.16
Found C 51.55, H 5.03, N 7.08, S 15.83
The ir and nmr spectra were in agreement with the -~
assigned structure. The nmr spectrum was quite characteristic
~`~ and differed appreciably From the starting amide. The nmr
(CDC13) spectrum had signals at ~1.23(s,3H), 1.73(s,3H), ~
CH3; 3.85(s,3H), COOCH3; 4.73(s,1H), C3-H; 4.95(s,2H), -OCH2-;
`1 5.20(d,1H, J=5cps), C5-H; 6.67 to 7.40(m,6H), C6H5 and C6-H;
9.78(d,1H), -CSNH-.
~ 30 The methyl penicillin V sulfoxide was collected in
;i~ later fractions.
. ~ . .
. . .
~ _ 1 1 _
:,'.' .
. ~ ....
-~ - . ~, . .
,y ~ vS~S
~ ~ - : . . .
~ "
63
.: '.
EXAMPLE 2
6-PHENOXYTHIOACETAMIDOPENICILLANIC ACID SULFOXIDE 3
(R = f~OCH2-, Rl = H)
.
Anhydrous penicillin V sulfoxide (1.098 g., 3
mmoles, prepared by drying penicillin V sulfoxide at 60C.
under vacuum over P205 to constant weight) and dimethylaniline
(1.14 ml., 9 mmoles) were dissolved in dry methylene chloride
(20 ml., dried by distillation over P205) and cooled to 0C.
Trimethylchlorosilane (0.418 ml., 3.3 mmoles) was added and
the yellow solution stirred for 30 mins at 0C. The mixture
was then cooled to ~30 and PC15 (0.685 9., 3.3 mmoles) added.
The mixture was stirred for 3 hours at -35 to -25, by which
time the mixture became a dark green colour. H2S was then
; passed through the stirred solution. On contact with H2S, the
. green colour was immediately discharged. After 30 mins the
temperature of the reaction mixture was raised to 0 by
. placing it in an ice-bath and, after stirring a further 30 ~ ~-
mins at th;s temperature,~the H25 addition was discontinued
and nitrogen was passed through the mixture which was diluted
with methylene chloride. The mixture was extracted with satu-
rated aqueous sodium bicarbonate (3 times, until the pH of the -~
aqueous layer was 8). The alkaline solut;on was then extract-
ed with ether (4 times) and then acidified to pH 2.0 with
,~ . , .
- hydrochloric acid (3 normal). At this stage some of the
. ;. . .
1 compound precipitated. The mixture was extracted with ethyl ~
i acetate (3 times). The combined organic extracts were washed -
`;~ with water, dried over Na2S04 and taken to dryness to give
,ll 0.73 g. of a yPllow solid, whose thin layer chromatogram and
ir and nmr spectra showed a mixture of the amide and thio-
amide. The 6-phenoxythioacetamidopenicillanic acid sulfoxide
.: ::~ , . . -
~, was estimated to be present in about 70% yield from the nmr
. ~.:...
~, . .
., ~.~ ,
-
~L~3~3~
spectrum. Purification of this thioamide can be effected by
column chromatography, using silicic acid.
EXAMPLE 3
6-PHENOXYTHIOCARBAMIDOPENICILLANIC ACID SULFOXIDF 3
(R - ~0-, Rl = H)
Aqueous potassium hydroxide (2 normal) was added
; slow1y to an ice-cold stirred suspension of 6~APA sulfoxide
(23.2 9., 0.1 mole) in water (275 ml), until a pH of 8Ø The
solution was diluted with THF (125 ml). The solution was
10 stirred in the ice-bath and separate solutions of phenoxythio- :
, . . .
carbamoyl chloride (17.2 g., 0.1 mole) in THF (50 ml.) and
aqueous KOH (2 normal) added by two separate dropping funnels
at such a rate as to maintain the pH constant at 8Ø The
;..................................................................... . ..
~`^ reaction mixture was stored in a refrigerator overnight and ~
. ~ . .
; then extracted with ethyl acetate (2 x 250 ml.). The water ~
, . . .
` layer was covered with ethyl acetate (150 ml.) in an ice-bath
`` and the pH adjusted to 1.5 with hydrochloric acid (12 normal).
.j The layers were separated and the aqueous layer extracted with
ethyl acetate (2 x 125 ml). The combined ethyl acetate layers
were dried over MgS04, concentrated and dried under vacuum to
eld 34.3 9. (92X) of~the crude 6-phenoxythlocarbamido-
peni;cillanic acid sulfoxide as a yellow brown foam.
The product was further purified by stirring with
~ ether (3 x 25 ml per gram of crude), filtering and discarding
-`~ the insoluble yellow solid. The ether filtrate was treated
with decolorizing charcoal,~filtered and concentrated to a
small volume. The white sol~id that separated (about 50%
~! recovery) had m.p. 153 - 156 (decomp), and nmr and ir spectra
t
in agreement with the proposed structure.
~ Analysis: Calcd. C 48.91, H 4.34, N 7.60, S 17.39
Found C 48.63, H 4.68, N 7.41, S 17.30
~ 13 ~
:~ . . .. .
.` :
EXAMPLE 4
METHOXYMETHYL 6-PHENOXYTHIOCARBAMIDOPENICILLANATE SULFOXIDE 3
(R = ~0, Rl = CH30CH2-) -
Chloromethylmethyl ether (2.66 g., 0.033 mole) wasadded slowly to an ice-cold stirred solution of 6-APA sulf-
oxide (6.96 g., 0.03 mole) and triethylamine (6.66 g., 0.066
mole) in methylene chloride (50 ml) and the reaction mixture
stirred in the ice-bath for l/2 hr. Phenoxythiocarbonyl
chloride (5.7 g., 0.033 mole) was then added slowly, when a
mild exothermic reaction (the temp rising to 5) occurred.
The reaction mixture was stirred an additional hour, by which
time the yellow solution containing a moderate amount of solid
had become almost clear and black. The reaction mixture was
washed with water (2 x 30 ml.), dried (MgS04 with added
decolorizing carbon) filtered and concentrated to ll g.
(88.7%) of a brown foam. The solid was stirred with ethyl
acetate (200 ml) for l/2 hr and filtered and the solid washed
with ethyl acetate. The combined filtrates on concentration
gave 8.4 g. (67.7%) of methoxymethyl 6-phenoxythiocarbamido-
penicillanate sulfoxide as a yellow foam whose ir and nmr
spectra were in agreement with the assigned structure.
EXAMPLE 5
METHYL 6-METHYLDITHIOCARBAMIDOPENICILLANATE SULFOXIDE 3
(R - CH~S and Rl = CH3) and 6-METHYLDITHIOCARBAMIDO-
PENICILLANIC ACID SULFOXIDE 3 (R = CH3S, Rl = H)
Carbon disulfide (3.35 g., 0.044 mole) was added to
an ice-cold stirred solution of 6-APA sulfoxide (9.28 g., 0.04
mole), and triethylamine (8.5 g., 0.084 mole) in dry DMF
'1 .,
, (25 ml). After l/2 hour stirring in the ice-bath, methyl
i3 :::
~`i 30 iodide (l2.4 g., 0.088 mole) was added, the mixture stirred an
~`~ addit;onal hour in the ice-bath and then stirred at ambient
temperature overnight (l6 hours). The solution was poured,
~ - l4 -
:~; . '
.
. , . . ~. .. . ~ . .. . . . : , .. : .. : . . .. : . . .::. . .
-, . . , . .: , . , i ,- , . , . .. . - ... ,,.. ,.. . . . . : . .. : . ... . ...
6~ -
,
with vigorous stirring into excess water when a sticky solid
separated. The solid was taken up in chloroform, the organic
layer washed with water (3 x 50 ml); dried over MgS04 with
decolorizing carbon, filtered, and the filtrate concentrated
to a brown foam 8.6 9., (62%). The nmr and ir spectra indi-
cated that the desired compounds were present in the product.
A tlc using ether as the developing solvent and iodine for
visualizing the components, indicated the presence of at least
four components.
The crude product (5.0 9.) was purified by chroma-
tography on silicic acid (250 g.) using ether as eluant and
collecting fractions (10 ml.). White crystals appeared in
many of the fractions 48 - 82, which all showed the same
component to be present by tlc. These crystals, from the nmr
spectrum were a mixture of the methyl 6-methyldithiocarbamido-
` penicillanate sulfoxide (II) and 6-methyldithiocarbamido-
penicillanic acid sulfoxide (II) in a ratio of about 2:1.
.,. , . ~ .
These fractions were combined and concentrated to give 2.7 g.
-~` of a brown foam whose nmr spectrum indicated a mixture of the
methyl ester and the acid in the ratio of about 1:1. A
'f. partial separation could be effected with ether. ;
The methyl ester was obtained pure by treating a
~ solution of the mixture in chloroform with aqueous sodium
-:~ bicarbonate, drying the organic layer and concentrating,
~`.3 whereby the methyl ester was obtained as a white foam, m.p.
138 - 142. The ir and nmr spectra were in agreement with the
assigned structure and the C,H values were within 0.4% of the
. calculated values.
` Analysis: Calcd. C 39.28, H 4.76
Found C 39.06, H 5.09
A high resolution mass spectral analysis of this
~ - 15 - ~
.. ~ , . .
~13~
compound gave a mass of 336.0268 for the parent ion. Calcu-
lated for CllH16N2S324 is 336-0273-
An attempt to recover the acid from the bicarbonatelayer was not successful.
EXAMPLE 6
METHOXYMETHYL 6-METHOXYMETHYLDITHIOCARBAMIDOPENICILLANATE
SULFOXIDE 3 (R = CH30CH2S and Rl = CH30CH2-)
; Carbon disulfide (1.7 g., 0.022 moles) was added to
an ice-cold, stirred solution of 6-APA sulfoxide (~.65 g.,
0.02 mole) and triethylamine (4.9 g., 0.04& mole) in methylene
chloride (65 ml), and the mixture stirred 1/2 hour in the ice-
bath and 1 hour at room temperature. The mixture was cooled
in an ice-bath and chloromethylmethyl ether (3.5 g., 0.044
mole) added dropwise over 1/2 hour. The reaction mixture was
stirred an additional hour in the ice-bath, then at room
temperature for i hour, finally cooled and washed rapidly with
ice-water (3 x 20 ml). The organic layer was dried (MgS04)
and concentrated to 6.1 9. of the methoxymethyl 6-methoxy-
methyldithiocarbamidopenicillanate sulfoxide as a sticky
yellow solid. The ir and nmr spectrum of thls compound were
in agreement with the assigned structure. The compound under-
went rapid hydrolysis with water and became quite sticky on
exposure to the air.
EXAMPLE 7
METHOXYMETHYL 6-METHYLDITWIOCARBAMIDOPENICILLANATE SULFOXIDE 3
(R`= CH3S, Rl = CH30CH2-)
Chloromethylmethyl ether (2.5 g., 0.03 mole) was "
`~ added to an ice-cold, s~tirred solution of 6-APA sulfoxide
(6.9 9., 0.03 mole~, and triethylamine (9.1 g., 0.09 mole) in
methylene chloride, and the react;on mixture stirred for an
additional 1/2 hour in the ice-bath. A mixture of carbon -
: . .~ .:- 16 - `
: :.
,. : . :
~, > .
~ - `
~)6~
disulfide (2.4 g., 0.03 mole) and methyl iodide (8.6 9., 0.06
mole) in methylene chloride (20 ml.) was added slowly to the
cold (10C) stirred reaction mixture, which was then stirred
an additional 2 hours at ambient temperature. The mixture was
stirred with water. (It was necessary to add an excess of
ethyl acetate to break the emulsion). The separated organic
layer was washed with water (2 times), dried over MgS04 with
decolorizing carbon, filtered through Celite~, and the
filtrate concentrated to a light yellow foam weighing 3.7 9.
(34%) which was the methoxymethyl 6-methyldithiocarbamido-
penicillanate sulfoxide.
EXAMPLE 8
TRIETHYLAMMO~IUM 6-METHYLAMINOTHIOCARBAMIDOPENICILLANATE
SULFOXIDE 3 (R = CH3NH, Rl = (C2H5)3NH)
, . . . .. .
Methylisothiocyanate (4.1 g., 0.055 mole) was added
to an ice-cold, stirred solution of 6-APA sulfoxide (11.6 9.,
0.05 mole), and triethylamine (11.1 9., 0.11 mole) in methyl-
ene chloride. The reaction mixture was stirred an additional
., .
; hour in the ice-bath, then for 2 hours at ambient temperature,
.i .
~ 20 then treated with decolorizing charcoal, filtered through
-',! ' Celite~ and taken to dryness. The resulting yellow foam was
~t triturated with ether, filtered, washed with ether and dried
at the pump to provide 19.7 9. (97%) of a flesh-colored powder
~. .
~! which was the triethylammonium 6-methylaminothiocarbamido- ~
. i
~ penicillanate sulfoxide. The ir and nmr spectra of the
u~ product were in agreement with the assigned structure.
. j ' .
,, ~ The triethylammonium salts were converted to esters,
~ such as the methyl esters, before the thermolysis to the
.~ 1,2,~-dithiaaz-3-enes. It is also possible to convert them to - -
.1 . . .
;~ 30 the trimethylsilyl esters prior to thermolysis. - -
. :
' . .' :
- 17 ~
,, '
~ . , ~
... . .
i3~
EXAMPLE 9
TRIETHYLAMMONIUM 6-PHENYLAMINOTHIOCARBAMIDOPENICILLANATE
SULFOXIDE 3 (R ~ ~NH, Rl = (C2H5)3NH)
.
Triethylammonium 6-phenylaminothiocarbamidopenicil-
lanate sulfoxide was made in the same way as in Example 8, by
the action of phenylisothiocyanate on 6-APA sulfoxide in the
presence of triethylamine. The compound was obtained as a
pale yellow powder, m.p. 145 - 148 (decomp) in 100% yield.
The ir and nmr spectra were in agreement with the assigned
structure.
The triethylammonium salts were converted to esters,
such as the methyl esters, before the thermolysis reactions.
It is also possible to convert them to the trimethylsilyl
esters prior to thermolysis.
~ ,.
.. . .
` ,
.
';,~' ' .''
:.'`'
.
, ,- -
',i : '. .
~ ... .
.. ~ . . .
:" ' :''
.
.
.~ ,:-
- 18 - -
-- .
' ~ ~
~6~
EXAMPLE lO
METHYL 6-PHENOXYTHIOAMIDOPENICILLANATE SULFOXIDE, 3
(R = 00, R' = CH3, R = H)
.
A solution oi 6-phenoxythioamidopenicillanic acid
sul~oxide in tetrahydro~uran was stirred ~n an ice~bath and a
solution o-~ diazomethane (l.2 equivalents) in ether added,
A~ter stirring in the ice bath an additional 15 minutes, the
resulting solution was treated with charcoal, ~iltered and
concentrated to dryness when a yellow ~oam resulted~ A very
small volume of methanol was added, whe~ the foam dissolved
readily. After a short tlme the methyl ester began to
crystallise as pale yellow crystals, The mixture was stirred
in an ice bath and the resultlng crystals lsolated in over ~0%
yield by ~iltration. The recrystalllsedmaterial, m~p. l~8 -
150 on masæ spectral analyæis gave a measured m/e o~ 382.0665,
while that calculated i'or Cl6H18N205S22 is 382.0658, The ir
and nmr spectra were consistent ~or the assigned structure.
The nmr spectrum (CDCl3~ ~8.32 (d, lH, NH), 7.59 to 7.05
(m, 5H, C6H5), 6,50 (q, lH, C6-H), 5.23 ~d, lH, C5-H3, 4.77
,
?`': ( S, lH, C3-H), 3.82 (s, 3H, COOCH3), l.70 and l.25 (ææ, 6H,
gem- CH3) iæ oharacteristic of this compound.
EXA~PLE ll
ETHYL 3-PHENOXYMETHYL-~,5-DITHIA-2,7-DIAZABICYCLO(4,2,0~)0CT-
ENE 8-ONE-7-ISOPROPENYLACETATE, 2 (R = ~OCH2, R2 _ H),~rom
MET~Y~ PEN~CIL~IN ~ OAMID~ SULF~IDE, ~ 00C~2, ~
,a~
~j
~, .,'! , :
A solution o~ pure methyl 6-pke~oxyth10a¢etamldo-
penicillanate sul~oxlde (500 mg., 1.3~moles) in toluene (125 ml)
was heated (in an oil bath at 120C) with stirring under reflux,
. ~ under nitrogen, in a ~lask ~itted with a Dean-Stark trap ~or 2
to 3~ hrs. The toluene was removed in vacuo. An nmr spectrum
1 9
- :
` i~63~
(CDC13) o~ the waxy residue showed complete reaction and
i'ormation o~ methyl 3-phenoxymethyl-4,5-dithia-2,7~diazabicyclo-
(4,2,0)oct-2-ene-8-one-7-isopropenylacetate, 2 (R = ~OOEI2, R' =
CH R2 = H), ~7.5 to 6.9 (m, 5H, C6H5), 5 72 (d, with wings,
2H, ~-lactam protons), 5.19 and 5.09 (ds, 2H, ~ 2), 4,95
(s, lH, CHCOOCH3), 4.87 (s, 2H, -OOEI2-), 3.8 (s, 3H, COOCH3),
~' 1.90 (s, 3H, ~ ). There was no trace of the ~,~ double
CH3
bond isomer in the nmr spectrum.
~ Exactly the same results are obtained by using
`~ purified dioxane in place o~ toluene as solvent. In this case,
instead of the Dean-Stark trap, the reaction ~lask was fit-ted
with a Soxhlet extractor, whose thimble is packed with a
~` drying agent such as magnesium sul~ate,
.:
~; In certain cases, particularly with old samples
o~ the thioamide, 3, thermolysis under the conditions described
above gave a mixture o~ products. It was ~ound that the
addition of dimethylaniline (preferably about ~ mole equivalent
per mole of th1oamide) before thermolysis gave a reproducible
~`; quantitative yield of the dithiazeneazetidinone, 2, on
thermolysis. The dimethylanillne could be removed from the
reaction product (in a toluene, methylene chldride, or chloro-
~orm solution) by rapid washing with aqueous dilute hydrochloric
aoid (O.5 normal).
,~ ~ : ::
~ ~ .
.`` : : .:
. : .
~ - 20 -
-: ` .: .
.;
~ , .
.~ . .
1 .
3~
EXAMPLE l2
METHYL 3-PHENOXYMETHYL-4,5-DITHIA-2,7-DIAZABICYCLO(4,2,0~0CT-
2-ENE-8-ONE-7-PROPENYLACETATE, 2 (R - ~OCH2, pl = CH3, R~ = H)
BY ISOMERISATION
The ~ double bond isomer, (200 mg., 0.505 mmoles)
was made by the method described in Example ll. The toluene
used as solvent was removed and immediately replaced by
purified tetrahydrofuran, the resulting solution being cooled
to -60C. Dimethylamine (23 mg., 0.505 mmoles) was added and
the reaction ~ixture kept at -60C for l/2 hour and then
concentrated ~n uacuo. The resulting product was the ~-
isomer, as shown by the nmr spectrum (CDCl3): ~7.47 to 6.82
(m, 5H, C6H5), 5.77 and 5.62 (ABq, J-5Hz, 2H, ~-lactam
protons), 4.84 (d, J=lHz, 2H, -0-CH2-), 3.77 (s, 3H, COOCH3),
; 2.24 and 2.02 (ss, 6H, =C(CH3)2).
EXAMPLE l3
.
METHYL 3-PHENOXYMETHYL-4-THIA-2,6-DIAZABICYCLO(3 2,0)HEPT-2-
j E~E-7-ONE-6~ISOPROPENYLACETATE, lb (R - 00CH2, Rl = CH~,
' R = H) BY THERMOLYSIS OF METHYL PENICILLIN V THIOAMID~
``i 20 SULFOXIDE 3, VIA 2 - -
-~ A solution of methyl penicillin V thioamide sulf-
oxide (0.5 g., l.26 mmoles) and ~s-(trimethylsilyl)trifluoro-
acetamide (0.36 g., l.40 mmoles) in purified dioxane (250 ml)
; was heated under reflux (in an oil bath at l20C) in an Argon atmosphere using a Soxhlet apparatus for the removal of
~;1 moisture (the Soxhlet thimble being packed with magnesium
:3~ sulfate). The course of the reaction was followed by removing, aliquots of the reaction mixture, concentrating to dryness and
obtaining nmr spectra. Estimations could be made by utilising
,
. ~ . .
,` ,: .
,
. ~ .
- 2l -
.
:: ,
. . . .
the characteristic signals of certain groups in the compounds.
Thus, the gem. dimethyl signals of` the penicillin sulfoxide
at ca. ~1.22 and 1.75, the ~ CH2 signal at ca. ~1.9 and
; the characteristic ~-lactam signals at ~5,72 characterised 2,
while lb was identified by its ~ CH2 singlet at ~1.75 and its
-- -3
~-lactam signals at ~6.0, amo~g others,
The following results were obtained:
Time o-f Estimated Percentage
Heating
Compound 3Compound 2b Compound lb
~: :
~ 1 hr 50% SO%
'` , 2 hr 38% 62%
` 3 hr 14% 80%
23 hr - 65% ~ 35%
30 hr - 50% 50%
48 hr - 10% 9o%
:
~ ~ It should be noted that throughout this thermolysis
. . .
there was no indication in the nmr spectra of any formation o~
the ~ lsomers la or 2a. Other experiments without added
silylating agents have shown that after 3~ to 4 hrs the
conversio~n of 3 to 2 is virtually complete, and no detectable
amounts of 1 are present, and with extended reaction times
compound lb is for~ed. This reaction is dependent on the
y~ thè s:olvent.
;j
. ~1 : : ~ ' ' . '.
'. ~: : ' :
.;
. .,
~ 22 -
~`
EX~MPLE 14
METHYL 3-PHENOXYMETEYL-4-THIA-2,6-DI~ZABICYLCO(3,2,0)HEPT-2-
ENE-7-ONE-6-ISOPROPENYLACETATE, lb, BY THE ACTION OF IODINE
_ND SODIU~ THIOSULFATE ON 2b
Methyl 3-phenoxymethyl-4,5-dithia-2,7-diaæabicylco-
(4,2,0)oct-2-ene-8 on~7~isopropenylacetate, 2b, reacted immed-
iately with iodine (1 atomic equivalent or 1 molar equivalent)
in organic solvents such as toluene or dioxane to give di-fferent
~` adducts (depending on the ratio) as was evident from the nmr
spectra of the residues. When these adducts in an organic
solvent s~lch as toluene or methylene chloride were stirred with
aqueous thiosulfates, they were converted in near quantitative
yields to compound lb, which was isolated by drying the organic
. ~ , .
` layer over magnesium sulfate, filtering and concentrating.
., .
Identity of the product was established by direct comparison
(ir and nmr spectra~ with an authentic sample of lb.
~" _XAMPLE 15
~.
, ,i
~ 3-PUENOXY-4,5-DITHIA-2,7-DIAZABICYCLO(4,2,0)0CT-2-ENE~8-~NE-
.~ 7-ISOPROPENYLACETIC ACID, 2b (R - 00, Rl = H, R~ = H)
, ~
A solution of 6-phenoxythiocarbamidopenicillanic
acid sulfoxide, 3 (R = 00, R = H, R2 = H) (15 g., 0.04 mole)
n purified dioxane (300 ml) was heated with stirring under ~ ;
re~lux in a dr~ nitrogen atmosphere in an oil bath maintained
at 130C, for~4 hrs. The rea~tlon mlx~ure was ooncentrated in
~ vaou~ ~nd drle~ un~ar hivaa. Th~ y~llowi3h brown~olid thu~
j~ obtatn~d wa~ di~olved in the minimum amount o~ warm ~e~one,
~ ~ .
the solution treated with ¢hàrcoal and filtered. The filtrate
was concentrated to about 1/3 its volume and just sufficient
hexane added to induce crystallization. The mlxture was
cooled overnight at about -10C and the resulting pale yellow
crystals isolated by filtration and drying, when 10.5 g (75%)
. . i .
~ - 23 -
.'~'........................................................................ .
of 3-phenoxy-4,5-dithia-2,7-diazabicyclo(4,2,0)oct-2-ene-8-
one-7-isopropenylacetic acid was obtained. The compound could
be purified by recrystallization from acetone-hexane. It was
obtained as white crystals, m.p. 1~6-148 dec. A high reso-
lution mass spectral analysis gave a mass of 350.0404 for the
parent ion, that calculated for C15H14N2S224 being 350-0396-
The nmr (DMSOd6) spectrum ~7.68 - 7.15 (m, 6H, C6H5 and COOH),
5.87 and 5.53 (ABq, 2H, J-5Hz, ~-lactam protons css-fused),
5.2 (s, 2H, ~ ), 4.85 (s, lH, -CHCOOH), 1.89
(s, 3H, ~ ) is in agreement with the assignment.
EXAMPLE 16
'~; METHYL 3-PHENOXY-4"~-DITHIA-2,7-DIAZABICYCLO(4,2,0)02T-2-ENE- ..
8-ONE-7-ISOPROPENYL~CETATE, 2b (R = ~0, Rl a CH3, R = H)
: -
3-Phenoxy-4,5-dithia-2,7-diazabicyclo(4,2,0)oct-2-
ene-8-one-7-isopropenylacetic acid (10.0 g., 28.5 mmole) was
dissolved in tetrahydrofuran (250 ml~ and the solution cooled
,
in an ice-bath. Excess of diazomethane in ether ~100 ml) was
added and the solution stirred in the ice-bath for 0.5 hr and
then concentrated in vacuo. The residue was taken up in the ~
minlmum of ether and cooled in a dry ice-acetone bath while ~ :
adding an equal volume of hexane. The resulting white pre-
cipitate was filtered off and dried to give 7.0 9 of the
product. A further 1.5 9., was obtained from the mother
liquor after concentration and repeating the ether-hexane
precipitation. The two crops were combined (8.5 9., 81%)
since they were identical (nmr spectra and tlc). The nmr
(CDC13) spectrum: ~7.6 to 7.1 (m, 5H, C6H5), 5.7 and 5.48
(ABq, 2H, J-4Hz, ~-lactam protons css-fused), 5.22 and 5.12
(d, s, 2H, ~ ), 5.0 (s, lH, CHCOOCH3), 3.8 (s, 3H,
.J
', ' "' . '
`~ - 24 - ~ ~
: ~ , . .
:', '' .~ :
106i3~
COOCH3), and 1.97 (s, 3H ~ ) is in agreement with the
assigned structure.
The same compound was also obtained by thermolysing
methyl 6-phenoxythioamidopenicillanate sulfoxide in toluene or
dioxane as solvent for about 4 hrs.
EXAMPLE 17
METHYL 3 PHENOXY-4-THIA-2,6-DIAZABICYCL~(3,2,0)HEPT-2-ENE-7-
ONE-6-ISOPROPENYLACETATE, lb (R = 00, Rl = CH , R2 = H) FROM
THE REACTION OF 2b WITH IODINE 3
A solution of methyl 3-phenoxy-4,5-dithia-2,7-diaza-
bicyclo(4,2,0)oct-2-ene-8-one-7-isopropenylacetate, 2b, (2 g.,
0.005 moles) in methylene chloride (50 ml~ was stirred with
` iodine (1.4 g., 0.005 moles) at ambient temperature for 12 hrs -
~ote: nmr spectra run on a similar reaction showed that this
. ~ .
reaction was comparatively slow and did not (unlike the
reaction with 2b (R = ~OCH2) in Example 14) require sodium
thiosulfate for the formation of lb. The sodium thiosulfate
was used in this reaction only to remove the iodin ~. The
` reaction mixture was washed with aqueous sodium thiosulfate
(2 x 50 ml), then water (2 x 50 ml), dried over magnesium
.
sulfate, filtered and concentrated to give 1.9 g., of a yellow
foam. The nmr spectrum (CDC13) of this foam showed the
`' presence of 2a (78%), mixed with the 3-iodocepham (22% -
~ characterized by the C3-CH3 singlet at ca. ~2.2 and the C2-CH2
`'~ quartet at ~3.0). The compound was purified by column chroma-
.i tography on Mallinckrodt SilicAr CC-7, using hexane:ether
~,' (1:1) as the eluant. The material crystallized from ether-
;.~ - .
~, hexane as floc~ulant silky white needles, m.p. 110 - 112.
:~l The nmr spectrum (CDC13) ~7.38 (br s, 5H, C6H5), 6.12 and 5072
, 30 (ABq, J=4Hz, 2H, ~-lactam protons e~s-stereochemistry), 5.22
, and 5.08 (br s, s, 2 ~ 2), 4.99 (s, lH, CHCOOCH3), 3.85 ~:
.,. . :~
- 25 -
.; '.,:
.. . . ~ . . , ., . . , ~ .. : , , ~ .
~: , . . . . , . ~ : .
~ - ~
3~
, :
( , , OCH3), 1.95 (s, 3H ~ CH )~ and mass spectrum -
Calc'd for C16H16N2532o4, 332.0831; measured 332.0826 with a
strong peak corresponding with M ~ 1, are in accordance with
the assigned structure.
EXAMPLE 18
METHYL 3-PHENOXY-4-THIA-2,6-DIAZABICYCLO(3,2,0)HEPT-2-ENE-7-
ONE-6-ISOPROPENYLACETATE, lb (R = ~0, Rl ~ CH , R2 - H) FROM
THE REACTION OF 2b with TI~TII)CHLORIDE 3
Hydrated stannous chloride (0.27 g., 6.86 x 10 4
mole) was added to a solution of methyl 3-phenoxy-4,5-dithia-
2,7-diazabicyclo(4,2,0)oct-2-ene-8-one-7-isopropenylacetate, `
2b (0.5 g., 6.86 x 10~4 mole) in dry tetrahydrofuran (10 ml),
cooled in an ice-bath. After stirring for 5 hrs, hydrogen
; sulfide was bubbled through the solution, which was then
filtered through Celite~ and concentrated, to give a brown
foam, whose nmr spectrum was characteristic of lb.
The same reaction was obtained in the added presence
of pyridine (0.109 9., 13.7 x 10 6 mole) during the reaction.
EXAMPLE 19
METHYL 3-PHENOXY-4-THIA-2,6-DIAZABICYCLq(3,2,0)HE2T-2-ENE-7-
ONE-6-ISOPROPENYLACETATE, lb (R ~ 00, R = CH~, R - H), FROM
THE REACTION OF 2b WITH ANTIMONY PENTACHLORID~
When equimolar quantities of antimony pentachloride
and 2b were-mixed at 0 in methylene chloride as solvent for
,
. 15 mins, the nmr spectrum of the concentrated product showed
. .,
~ the characteristic spectrum of lb.
. ~ .
EXAMPLE 20
` METHYL 3-PHENOXY-4-THIA-2,6-DIAZABICYCL10(3,2,0)HEPT-2-ENE-7- ~ ~
ONE-6-ISOPROPENYLACETATE, lb (R = ~0, R ~ CH ~ R2 = H) FROM -
` 30 THE REACTION OF 2b WITH SULFENYL IODIDES 3
~ ~;
A ~ixture of methyl 3-phenoxy-4,5-dithia-2,7-diaza- :
`~ bicyclo(4,2,0)oct-2-ene-8-one-7-isopropenylacetate (200 mg.,
0.55 mmoles), 2-mercaptobenzothiazole (138 mg., 0.825 mmoles)
~i,, ' ~ " :' -: '
- 26 - ~
., ,,: :
3~
and iodine (419 mg., 1.65 mmoles) in methylene chloride
(15 mls) was stirred at room temperature overnight. The :.
reaction product was taken to dryness. The nmr spectrum of
the residue showed it to be the sulfur extruded compound,
methyl 3-phenoxy-4-thia-2,6-diazabicyclo(3,2,0)hept-2-ene-7-
one-6~isopropenylacetate, formed in essentially quantitative
yields.
: .
. In a similar manner starting from trichloroethyl
3-phenoxy-4,5-dithia-2,7-diazabicyclo(4,2,0)oct-2-ene-8-one-7-
. . .
1 a isopropenylacetate, benzhydryl 3-phenoxy-4,5-dithia-2,7-diaza- ~ . .
bicyclo(4,2,0)oct-2-ene-8-one-7-isopropenylacetate, trimethyl~
.~ silyl 3-phenoxy-4,5-dithia-2,7-diazabicyclo(4,2,0)oct-2-ene-8-
` one-7-isopropenylacetate, trichloroethyl 3-(2',6'-dimethoxy- ~ -
phenyl)-4,5-dithia-2,7-diazabicyclo(4,2,0)oct-2-ene-8-one-7- .
isopropenylacetate, benzyl 3-(3'-phenyl-5'-methylisoxazolyl)- ::
.
i 4,5-dithia-2,7-diazabicyclo(4,2,0)oct-2-ene-8-one-7-iso-
propenylacetate, and trichloroethyl l-methoxy-3-phenoxymethyl- .
s 4~5-dithia-2,7-diazabicyclo(4,2,0)oct-2-ene-8-one-7-iso- ..
:............ propenylacetate, it is possible to prepare trichloroethyl 3- .
.: .
20. phenoxy-4-thia-2,6-diazabicyclo(3,2,0)hept-2-ene-7-one-6-iso- .
propenylacetate, benzhydryl 3-phenoxy-4-thia-2,6-diazabicyclo- ~ ..
(3,2:,0)hept-2-ene-7-one-6-isopropenylacetate, trimethylsilyl ... :.
~ 3-phenoxy-4-thia-2,6-diazabicyclo(3,2~0)hept-2-ene-7-one-6-
-.-j isop~ropenylacetate, 3-phenoxy-4-thia-2,6-diazabicyclo(3,2,0)-
l hept-2-ene-7-one-6-isopropenyl acetic acid, trichloroethyl 3-
'1 .
(2',6'-dimethoxyphenyl)-4-thia-diazabicyclo(3,2,0)hept-2-ene-
7-one-6-isopropenylacetate, benzyl 3-(3'-phenyl-5'-methyl- ~.
`~ isoxazolyl)-:4-thia-2,6-diazabicyclo(3,2,0)hept-2-ene-7-one-6-
isopropenylacetate, and trichloromethyl l-methoxy-3-phenoxy- .
methyl-4-thia-2,6-diazabicyclo(3,2,0)hept-2-ene-7-one-6-iso- .-
~;~ propenylacetate. : ~
.
~ - 27 -
: ~.
~ ()G3~
EXAMPLE 21 i~
METHYL 7-PHENOXYACETAMIDO-3-METHYL-3-IODOCEPHAM-4-CARBOXYLATE
FROM METHYL 3-PHENOXYMETHYL-4-THIA-2,6-DIAZABICYCLO(3,2,0)-
HEPT-2-ENE-2-ONE-6-ISOPROPENYLACETATE, lb (R = ~OCH2,
Rl = CH3, R = H
A mixture of methyl 3-phenoxymethyl-4-thia-2,6-
diazabicyclo(3,2,0)hept-2-ene-7-one-6-isopropenylacetate, lb,
and iodine (1 molar equivalent) in methylene chloride were
` stirred at ambient temperature for 16 hrs while moist air was
bubbled through. The dark brown residue after concentration
was taken up in chloroform, washed with aqueous sodium thio-
sulfate (twice), then ~ater (twice) and dried over magnesium
sulfate. The nmr spectrum of the residue from the filtrate
showed the presence of about 25% of the 3-iodocepham compound.
The presence of this compound was confirmed by thin layer
chromatography.
Heating the 3-iodocepham for 1 hr in benzene con-
taining pyridine gave an about 75% yield of methyl 7-phenoxy-
acetamido-3-methylceph-3-ene-4-carboxylate.
EXAMPLE 22
METHYL 7-PHENOXYACETAMIDO-3-METHYL-3-IODOCEPHAM-4-CARBOXYLATE,
4 (R = ~OC~l2, R2 = H, Rl = CH3) FROM METHYL 3-PHENOXYMETHYL-4-
THIA-2,6-DIAZABICYCLO ~,2,~HEPT-2-ENE-7-ONE-6-ISOPROPENYLACE-
TATE, 1 (R = ~OCH , R~ ~ H, Rl = CH3) USING SULFENYL IODIDES
.. ~
~ IODINE-WATER
;1. 2-Mercaptobenzothiazole (70.2 mg., 0.42 mmoles) and
1 ~
, iodine (213 mg., 0.84 mmoles) were added to a stirred solution
.~
of methyl 3-phenoxymethyl-4-thia-2,6-diazabicyclo~ ,2, ~hept-
2-ene-7-one-6-isopropenylacetate (100 mgs., 0.28 mmoles) in
methylene chloride (15 ml), and the mixture stirred at ambient
; temperature for 15 mins. Water (15 mls) was then added and
.''J the mixture stirred overnight at room temperature. The
organic layer was separated, dried over magnesium sulfate,
' - 28 - -
' ',, , ': ' .
.. :. ~. '.:
: . . ... . . . .. . . .. . .... .. ..... . . . . . . . . .
, ~, . - ... , .. .. . . ., , .. .. : . : .
, - , , : , , ,
filtered and concentrated. The nmr spectrum of the residue
showed the presence of about 80% of the 3-iodocepham.
In a similar manner using the thio-compounds such as
thioacetamide, thioacetanilide, thiourea, N,N'-dimethylthio-
urea, N,N'-diphenylthiourea, t-butyl mercaptan, isopropyl-
mercaptan, thiophenol, p-chlorothiophenol, ethyl 2-mercapto-
acetate, 2-mercaptobenzooxazole, 2-mercaptobenzimidazole, 2-
mercaptothiazolene, triphenylmethylmercaptan, benzylmercaptan,
dimethyl disulfide, dibenzyldisulfide, di-t-butyldisulfide,
10 di-p-tolyldisulfide, thioacetic acid and thiobenzoic acid and ;
the following compoundsi
trichloroethyl 3-phenoxymethyl-4-thia-2,6-diazabicyclo ~,2,~-
. hept-2-ene-7-one-6-isopropenylacetate,
p-nitrobenzyl 3-phenoxymethyl-4-thia-2,6-diazabicyclo ~ ,2, ~-
!,
hept-2-ene-7-one-6-isopropenylacetate, -
trichloroethyl 3-benzyl-4-thia-2,6-diazabicyclo~ ,2, ~hept-2-
ene-7-one-6-isopropenylacetate,
p-nitrobenzyl 3-benzyl-4-thia-2,6-diazabicyclo ~,2, ~hept-2-
, , .
;~' ene-7-one-6-isopropenylacetate, and
.. . . .
`~ 20 trichloroethyl 1-methoxy-3-phenoxymethyl-4-thia-2,6-diaza-
` bicyclo ~,2,~hept-2-ene-7-one-6-isopropenylacetate,
.~.
` it is possible to obtain;
trichloroethyl 7-phenoxyacetamido-3-methyl-3-iodocepham-4-
carboxylate,
.:~1 . .
i~i p-nitrobenzyl 7-phenoxyacetamido-3-methyl-3-iodocepham-4-
~ carboxylate,
:~ .
, trichloroethyl 7-phenylacetamido-3-methyl-3-iodocepham-4-
-~ ~ carboxylate,
~ p-nitrobenzyl 7-phenylacetamido-3-methyl-3-iodocepham-4-
. . .
~ 30 carboxylate, and -
'-s ' ~
. . .. .
-
~)63t~ ~
trichloroethyl 7-methoxy-7-phenoxyacetamido-3-methyl-3-iodo-
cepham-4-carboxylate.
EXAMPLE 23
METHYL 7-PHENOXYACETAMIDO-3-METHYLCEPH-3-EM-4-CARBOXYLATE FROM
METHYL 7-PHENOXYACETAMIDg-3-METHYL-3-IODOCEPHAM-4-CARBOXYLATE,
4 (R = ~OCH2-, R2 - H, Rl = CH3), USING PYRIDINE IN BENZENE
_ _ .
A solution of methyl 7-phenoxyacetamido-3-methyl-3-
iodocepham-4-carboxylate and pyridine in benzene was heated
under reflux, in an oil-bath maintained at 90. Periodically
aliquots of the reaction mixture were removed and the progress
of the reaction followed by analyzing the nmr spectrum of the
residue. The 3-iodocepham in the mixture is characterized by
;~ the C4-H singlet at ~4.9, the C6-H doublet at ~5.38 and the
C2-CH2 quartet at ~2.95; the ceph-3-em is characterized by its
'i C6-H doublet at ~5.05 and its C2-CH2 doublet at ~3.35. Anyceph-2-em produced is easily detected by its C3-CH3 singlet at
~1.92 and its C2-H signal at ~6.1. In all our experiments
using pyridine as the base there were no detectable amounts of
the ceph-2-em isomer produced. The following table summarizes
the results of experiments in which the relative amount o~
pyridine was varied.
. . .
.
. .
.,~'` . .
.~ ' '
~, ... .
: .
'
,, . .:
- 30 -
' ;'
, ':
.. , .. . . .; . - .. , - . . .... i . : . . . . . -.. .. - . :. ~ . - .
~l~63~
TABLE 1
Dehydroiodination of 3-1odocepham usin~ Pyridine in Benzene
No. Mole Ratio of Pyridine Time of Reflux Yield of Ceph-3-em(~)
1. 2.5 equivalents 0.5 hr 45
2. 2.5 " 1.0 hr 60
3. 2.5 " 1.5 hr 67
4. 5 equivalents 0.5 hr 50
5. 5 " 1.0 hr 66
6. 5 " 1.5 hr 80
107. 5 " 3.0 hr ~100
8. 10 equivalents 0.5 hr 60
9. 10 " 1.0 hr ~100
10. 10 " 1.5 hr 100
* There was no detectable trace of any ceph-2-em isomer in any
of these experiments.
EXAMPLE 24
". :, .
` METHYL 7-PHENOXYACETAMIDO-3-METHYLCEPH-3-EM-4-CARBOXYLATE FROM
METHYL 7-PHENOXYACETAMIDO-3-METHYL-3-IODOCEPHAM-4-CARBOXYLATE,
` 4 (R - ~OCH2-, R2 = H, Rl = CH3) USING PYRIDINE ALONE
~ 20 Methyl 7-phenoxyacetamido-3-methyl-3-iodocepham-4-
; carboxylate (100 mg) was dissolved in pyridine d5 (0.5 ml) and
~; the reaction monitored by running an nmr spectrum on the
~; sample periodically. After about 15 mins at ambient tempera-
; ture there was about 50%,conversion to the ceph-3-em, and
after 2 hrs the reaction was complete. The nmr spectrum did :
,, - . . .
~ not change after a 24-hour period and again no detectable
;~ amount of the ceph-2-em isomer was observed.
:.
. ' ':
' ," . . .
' - 31 -
~,
